Identification of CD14 and lipopolysaccharide-binding protein as novel biomarkers for sarcoidosis using proteomics of serum extracellular vesicles.

Sarcoidosis is a complex, polygenic, inflammatory granulomatous multi-organ disease of unknown cause. The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. Extracellular vesicles (EVs) play important roles in intercellular communication. We subjected serum EVs, isolated by size exclusion chromatography, from seven patients with sarcoidosis and five control subjects to non-targeted proteomics analysis. Non-targeted, label-free proteomics analysis detected 2292 proteins in serum EVs; 42 proteins were up-regulated in patients with sarcoidosis relative to control subjects; and 324 proteins were down-regulated. The protein signature of EVs from patients with sarcoidosis reflected disease characteristics such as antigen presentation and immunological disease. Candidate biomarkers were further verified by targeted proteomics analysis (selected reaction monitoring) in 46 patients and 10 control subjects. Notably, CD14 and lipopolysaccharide-binding protein (LBP) were validated by targeted proteomics analysis. Up-regulation of these proteins was further confirmed by immunoblotting, and their expression was strongly increased in macrophages of lung granulomatous lesions. Consistent with these findings, CD14 levels were increased in lipopolysaccharide-stimulated macrophages during multinucleation, concomitant with increased levels of CD14 and LBP in EVs. The area under the curve values of CD14 and LBP were 0.81 and 0.84, respectively, and further increased to 0.98 in combination with angiotensin-converting enzyme and soluble interleukin-2 receptor. These findings suggest that CD14 and LBP in serum EVs, which are associated with granulomatous pathogenesis, can improve the diagnostic accuracy in patients with sarcoidosis.

Diagnostic and Staging Value of Serum Angiotensin-Converting Enzyme in Sarcoidosis.

OBJECTIVE: To investigate the diagnostic and staging value of serum angiotensin-converting enzyme (sACE) in sarcoidosis. METHODS: Patients with suspected sarcoidosis treated in the Department of Pulmonary and Critical Care Medicine of the China-Japan Friendship Hospital from 2010 to 2020 were included. The data of sACE, erythrocyte sedimentation rate (ESR), complete blood count (CBC), lung function, bronchoalveolar lavage, and biopsy were collected. The differences between the sarcoidosis group and the nonsarcoidosis group and between different stages of sarcoidosis were compared. The receiver operating characteristic (ROC) curve analysis was used for the diagnostic test of sACE in sarcoidosis. RESULTS: A total of 84 cases with suspected sarcoidosis were included, among which 70 cases were confirmed to be sarcoidosis by biopsy. The mean value of sACE in sarcoidosis patients was 56.61 ± 30.80 U/L, which was significantly higher than that in nonsarcoidosis patients (28.07 ± 14.11 U/L, P = 0.001). The level of sACE in sarcoidosis patients with peripheral superficial lymph nodes and multiple system involvement was significantly higher than that in intrathoracic sarcoidosis patients (P = 0.009); the percentage of lymphocytes in bronchoalveolar lavage fluid (BALF) of sarcoidosis patients was 45.39 ± 22.87%, which was significantly higher than that of nonsarcoidosis patients (P < 0.001). There was no correlation between sACE and ESR (correlation coefficient = -0.167). According to ROC curve analysis, when sACE ≥ 44.0 U/L, the sensitivity of sarcoidosis diagnosis was 61.4%, the specificity was 92.9%, and the AUC was 0.819. CONCLUSION: sACE has a good specificity in the diagnosis of sarcoidosis. sACE values in patients with sarcoidosis with systemic involvement were higher than those with simple intrathoracic sarcoidosis.

Tofacitinib effectiveness in Blau syndrome: a case series of Chinese paediatric patients.

OBJECTIVE: Blau syndrome (BS), a rare, autosomal-dominant autoinflammatory syndrome, is characterized by a clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis and associated with mutations of the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Aim of this study was to assess the efficacy of tofacitinib in Chinese paediatric patients with BS. METHODS: Tofacitinib was regularly administered to three BS patients (Patient 1, Patient 2, and Patient 3) at different dosages: 1.7 mg/day (0.11 mg/kg), 2.5 mg/day (0.12 mg/kg), and 2.5 mg/day (0.33 mg/kg). The clinical manifestations of the patients, magnetic resonance imaging results, serological diagnoses, therapeutic measures and outcomes of treatments are described in this report. RESULTS: The clinical characteristics and serological diagnoses of all BS patients were greatly improved after the administration of tofacitinib treatment. All patients reached clinical remission of polyarthritis and improvements in the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and inflammatory cytokines. CONCLUSION: Tofacitinib, a Janus kinase (JAK) inhibitor, is a promising agent for BS patients who have unsatisfactory responses to corticosteroids, traditional disease-modifying antirheumatic drugs, and biological agents.

Cytokine Signaling and Matrix Remodeling Pathways Associated with Cardiac Sarcoidosis Disease Activity Defined Using FDG PET Imaging.

While cardiac imaging has improved the diagnosis and risk assessment for cardiac sarcoidosis (CS), treatment regimens have consisted of generalized heart failure therapies and non-specific anti-inflammatory regimens. The overall goal of this study was to perform high-sensitivity plasma profiling of specific inflammatory pathways in patients with sarcoidosis and with CS.Specific inflammatory/proteolytic cascades were upregulated in sarcoidosis patients, and certain profiles emerged for CS patients.Plasma samples were collected from patients with biopsy-confirmed sarcoidosis undergoing F-18 fluorodeoxyglucose positron emission tomography (n = 47) and compared to those of referent control subjects (n = 6). Using a high-sensitivity, automated multiplex array, cytokines, soluble cytokine receptor profiles (an index of cytokine activation), as well as matrix metalloproteinase (MMP), and endogenous MMP inhibitors (TIMPs) were examined.The plasma tumor necrosis factor (TNF) and soluble TNF receptors sCD30 and sTNFRI were increased using sarcoidosis, and sTNFRII increased in CS patients (n = 18). The soluble interleukin sIL-2R and vascular endothelial growth factor receptors (sVEGFR2 and sVEGFR3) increased to the greatest degree in CS patients. When computed as a function of referent control values, the majority of soluble cytokine receptors increased in both sarcoidosis and CS groups. Plasma MMP-9 levels increased in sarcoidosis but not in the CS subset. Plasma TIMP levels declined in both groups.The findings from this study were the identification of increased activation of a cluster of soluble cytokine receptors, which augment not only inflammatory cell maturation but also transmigration in patients with sarcoidosis and patients with cardiac involvement.

Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype.

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

Multiple firm nodules in a young woman: an unusual presentation of sarcoidosis.

A 27-year-old woman presented to the dermatology department with a 1-year history of multiple asymptomatic violaceous lesions on her upper and lower extremities, trunk and abdomen. The lesions were firm on palpation. She had no other associated symptoms and the rest of the examination was unremarkable. An incisional biopsy showed multiple confluent granulomas composed of histiocytes devoid of necrosis surrounded by a rim of lymphocytes extending to the subcutaneous fat consistent with the diagnosis of subcutaneous sarcoidosis. The serum ACE assay was elevated at 134 IU/L. Other blood tests including complete blood count, renal and liver function tests, serum calcium and phosphate were within normal ranges and chest X-ray was unremarkable. Complete remission was achieved with an intralesional triamcinolone injection (10 mg/mL) for a few sessions. Subcutaneous sarcoidosis is a rare variation and its diagnosis requires a high index of suspicion.

Local and Systemic Concentrations of Pattern Recognition Receptors of the Lectin Pathway of Complement in a Cohort of Patients With Interstitial Lung Diseases.

Background: The role of the lectin pathway of complement in the pathogenesis of interstitial lung diseases (ILDs) is largely unknown. Pattern recognition receptors (PRR) of the lectin pathway are involved in the clearance of apoptotic cells either via activation of the complement system or as direct opsonins. As recent findings suggest a role of apoptosis in the development of pulmonary fibrosis, the influence of plasma lectins has lately been considered in various ILDs, but data on local concentrations in the lungs are lacking. This study investigated the role of mannose-binding lectin (MBL), ficolin-2 and ficolin-3 in ILD patients with a focus on idiopathic pulmonary fibrosis (IPF) and sarcoidosis. Methods: A case control study was conducted involving 80 patients with different forms of ILD as well as 40 control patients undergoing routine flexible bronchoscopy with bronchoalveolar lavage (BAL). Plasma and BAL fluid (BALF) levels of MBL, ficolin-2 and ficolin-3 as well as complement split products C4d and C5a (only in BALF) were measured by enzyme-linked immunosorbent assays. Eight single-nucleotide polymorphisms (SNPs) of MBL and ficolin-2 were determined by genotyping and tested for their association with ILDs. Results: We included 35, 35, 10, and 40 patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF), other ILD, and a control group, respectively. BALF but not plasma levels of the three PRR were significantly elevated in sarcoidosis patients compared to a control group without ILD (MBL: median 66.8 vs. 24.6 ng/ml, p = 0.02, ficolin-2: 140 vs. 58.8 ng/ml, p = 0.01, ficolin-3: 2523 vs. 1180 ng/ml, p = 0.02), whereas the frequency of the investigated SNPs was similar. In line, complement split products were markedly elevated in BALF of sarcoidosis patients (C4d, median 97.4 vs. 0 ng/ml, p = 0.10; C5a, 23.9 vs. 9.1 ng/ml, p = 0.01). There was a weak positive correlation of BALF ficolin-3 with serum neopterin, a marker of sarcoidosis activity. In IPF patients, we observed numerically higher MBL plasma and BALF levels (plasma, median 1511 vs. 879 ng/ml, p = 0.44; BALF, 37.5 vs. 24.6 ng/ml, p = 0.7) as well as lower ficolin-2 plasma levels (plasma 1111 vs. 1647 ng/ml, p = 0.11). Ficolin-2 plasma levels were inversely correlated with the forced vital capacity (r = 0.55, p = 0.1). Conclusion: This is the first study to simultaneously assess systemic and local lectin pathway protein levels in ILD patients. Our data suggest an involvement of PRR of the lectin pathway in the pathogenesis of sarcoidosis given the significantly higher BALF levels compared to a control group. Additional analyses in a larger patient cohort are required to confirm or refute a potential effect of local and/or systemic ficolin-2 levels in IPF patients.

The Association of Neutrophil/Lymphocyte and Platelet/Lymphocyte Ratios and Hematological Parameters with Diagnosis, Stages, Extrapulmonary Involvement, Pulmonary Hypertension, Response to Treatment, and Prognosis in Patients with Sarcoidosis.

Sarcoidosis is a rare disease characterized by granulomatous inflammation in affected organs, primarily in lungs. Neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) are easy and practical methods providing valuable information in diagnosis, severity, and prognosis of various diseases. Here, we aimed to investigate the association between NLR, PLR, and hematological parameters in sarcoidosis. The study was performed with 75 sarcoidosis patients and 92 controls. Patients' NLR, PLR, and hematological parameters were compared with those of controls. Additionally, while differences between NLR and PLR were investigated in sarcoidosis patients, differences of extrapulmonary involvement, pulmonary hypertension (PH), and spontaneous remission between those with and without responses to treatment concerning stages were also assessed. NLR and PLR were significantly higher in sarcoidosis patients than controls. For NLR, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were found as 68, 61, 58, and 70% respectively, while sensitivity, specificity, PPV, and NPV for PLR were found as 72, 67, 63, and 74%, respectively. In sarcoidosis patients, NLR and PLR were significantly higher at stage-2 and -3 than at stage -1 and -4. There was a significant weak positive correlation between C-reactive protein (CRP) and NLR and PLR. Mean platelet volume (MPV), hemoglobin (Hgb), and mean corpuscular volume (MCV) were lower among patients than controls. A positive moderate correlation was detected between NLR and CD4/CD8 in blood, while there was a strong positive correlation between CD4/CD8 in bronchoalveolar lavage (BAL) and positive moderate correlation between PLR and CD4/CD8 in BAL. High NLR and PLR values were not significantly associated with pulmonary PH, spontaneous remission, response to treatment, and prognosis. The increase in PLR and NLR may be a guide for diagnoses of both sarcoidosis and lung parenchymal involvement. To use these entities as markers, our findings should be supported with prospective studies with larger samples.

Oxaliplatin-associated sarcoid-like reaction masquerading as recurrent colon cancer.

A 54-year-old man with stage IV B metastatic colorectal cancer with liver and peritoneal metastasis was treated with cytoreductive surgery (extended left colectomy, right partial hepatectomy, resection of right diaphragm nodule) and perioperative oxaliplatin-based chemotherapy. The patient was cancer-free for 6 months, at which point a surveillance positron emission tomography-CT scan showed metabolically active hepatosplenic lesions and mediastinal and bilateral hilar lymph nodes. An endobronchial ultrasound bronchoscopy-guided fine needle aspiration of the mediastinal and hilar lymph nodes revealed non-necrotising granulomas. The workup was negative for bacterial, fungal or mycobacterial infection, cancer or autoimmune disease. Carcinoembryonic antigen and COLVERA (a circulating tumour DNA liquid biopsy test for the detection of recurrent colon cancer) tests were negative. Subsequently the rare diagnosis of a sarcoidosis-like reaction from oxaliplatin-based chemotherapy was made. Repeat imaging after 3 months showed resolution of the hepatosplenic lesions and lymphadenopathy, alike.

The Burden of Neurosarcoidosis: Essential Approaches to Early Diagnosis and Treatment.

Neurosarcoidosis (NS) is an often severe, destructive manifestation with a likely under-reported prevalence of 5 to 15% of sarcoidosis cases, and in its active phase demands timely treatment intervention. Clinical signs and symptoms of NS are variable and wide-ranging, depending on anatomical involvement. Cranial nerve dysfunction, cerebrospinal parenchymal disease, aseptic meningitis, and leptomeningeal disease are the most commonly recognized manifestations. However, non-organ-specific potentially neurologically driven symptoms, such as fatigue, cognitive dysfunction, and small fiber neuropathy, appear frequently.Heterogeneous clinical presentations and absence of any single conclusive test or biomarker render NS, and sarcoidosis itself, a challenging definitive diagnosis. Clinical suspicion of NS warrants a thorough systemic and neurologic evaluation hopefully resulting in supportive extraneural physical exam and/or tissue findings. Treatment targets the severity of the manifestation, with careful discernment of whether NS reflects active potentially reversible inflammatory granulomatous disease versus inactive postinflammatory damage whereby functional impairment is unlikely to be pharmacologically responsive. Non-organ-specific symptoms are poorly understood, challenging in deciphering reversibility and often identified too late to respond to conventional immunosuppressive/pharmacological treatment. Physical therapy, coping strategies, and stress reduction may benefit patients with all disease activity levels of NS.This publication provides an approach to screening, diagnosis, disease activity discernment, and pharmacological as well as nonpharmacological treatment interventions to reduce disability and protect health-related quality of life in NS.

[Measurement of angiotensin-I-converting enzyme in the blood: help for method validation]. / Dosage de l'enzyme de conversion de l'angiotensine-I sanguine : aide à la validation de méthode.

Blood angiotensin-converting enzyme (ACE) assay is now realized by the determination of enzyme activity on synthetic substrate, mostly furylacryloyl-phenylalanyl-L-glycyl-L-glycine (FAPGG). The matrix can be serum or heparin-plasma, with or without a separator; the assay developed on serum or plasma is not adapted to other matrix such as cerebrospinal fluid where the ACE activity is much lower. This assay has been adapted on a number of automated biochemistry analyzers with the specifications of the supplier of reagents, sometimes with modification of volumes or times for analysis. Samples can be stored at +4̊C for at least for one week, freezing at -20̊C is possible but refreezing is not advised. The assay is linear from 10 to 200 UI/L. Fidelity is excellent after calibration of the assay. Accuracy can be calculated from IQA and EQA results, and the analytical uncertainty is between 2% and 5% in function of the serum ACE value. Usual values will be soon available from studies on age brackets and sex, because ACE activity seems to be more elevated in boys during adolescence. At signature, it is interesting to have medical information on the diagnosis of sarcoidosis or its treatment including ACE inhibitors as a proof of intake; we can give a commentary on elevation of serum ACE activity from other causes than sarcoidosis and the causes for low activities.

Serum IL-35 Levels Are Associated With Activity and Progression of Sarcoidosis.

Objective: To investigate the relationship of interleukin (IL)-35 with sarcoidosis. Methods: We enrolled 114 inpatients and outpatients with sarcoidosis at the Shanghai Pulmonary Hospital, and 24 healthy controls between March 2015 and December 2017. Serum and whole blood were collected during the follow-up period. Serum IL-35 levels were detected by ELISA. Proportions of Breg, Tfh, and Treg cells in the peripheral blood were detected using flow cytometry (FCM). The mRNA levels of p35, EBI3, and GAPDH in CD19+ cells and CD4+ cells were detected by real-time PCR. Sarcoidosis granuloma mice models were established with Propionibacterium acnes (PA) and one group was treated with IL-35 antibodies. Proportions of Breg, Tfh, and Treg cells in the peripheral blood and bronchoalveolar lavage fluid (BALF) were detected by FCM. Results: The IL-35 levels and the proportions of Breg and Tfh cells in the peripheral blood of patients with active sarcoidosis were significantly higher compared to patients with stable sarcoidosis and healthy controls. Moreover, the IL-35 level in patients with progressive disease was lower than that found at the initial visit. EBI3 and p35 mRNA levels in CD19+ cells for patients with active sarcoidosis were significantly higher as compared to patients with stable sarcoidosis and healthy controls, while there were no significant differences in p35 and EBI3 mRNA levels in CD4+ cells between the three groups. In the mouse model of sarcoidosis, there were loose granulomata (macrophage accumulation in the bronchial areas and immature granuloma) after intervention with IL-35 antibodies. Meanwhile, the proportions of Breg cells in the peripheral blood and BALF of the model were significantly increased, while the proportion of Treg cells declined significantly. After intervention with IL-35 antibodies, the proportion of Breg cells in the peripheral blood of mice decreased significantly as compared to the mice not exposed to anti-IL-35 antibodies. Conclusion: IL-35 levels increased significantly in the serum of patients with active sarcoidosis, and lower IL-35 levels were correlated with persistent disease. Serum IL-35 levels might be better correlated with Breg cell functions.

Relevance of concurrent hypercalcemia in ureteric sarcoidosis complicated with bladder urothelial carcinoma: a case report.

BACKGROUND: Sarcoidosis is a multisystem inflammatory disorder and can affect any organ; however, ureteric involvement is extremely rare with only four cases reported in the literature to date, all of which were diagnosed with surgical ureteral resection including a nephroureterectomy. This study reports the first case of ureteric sarcoidosis controlled with medical therapy where a differential diagnosis was performed based on the diagnostic clue of hypercalcemia. A definitive diagnosis was established without surgical resection of the ureter. CASE PRESENTATION: A 60-year-old man presented with anorexia and weight loss. Blood tests showed renal dysfunction and hypercalcemia. Computed tomography revealed left hydronephrosis associated with left lower ureteral wall thickening, which showed high signal intensity on diffusion-weighted magnetic resonance imaging. Similarly, we detected a bladder tumor on cystoscopy, and a 2-cm-long stenosis was revealed by retrograde ureterography; therefore, ureteral cancer was suspected. Meanwhile, considering the clinical implication of hypercalcemia, a differential diagnosis of sarcoidosis was established based on elevated levels of sarcoidosis markers. Fluorodeoxyglucose positron emission tomography showed fluorodeoxyglucose accumulation in the left lower ureter, skin, and muscles, suggestive of ureteric sarcoidosis with systemic sarcoid nodules. For a definitive diagnosis, transurethral resection of the bladder tumor and ureteroscopic biopsy were performed. Histopathological examination revealed ureteric sarcoidosis with bladder urothelial carcinoma. Following an oral administration of prednisolone, hypercalcemia instantly resolved, the renal function immediately improved, and the left ureteral lesion showed complete resolution with no recurrence. CONCLUSIONS: In this case, the co-occurrence of ureteral lesion with bladder tumor evoked a diagnosis of ureteral cancer. However, considering a case of ureteral lesion complicated with hypercalcemia, assessment for differential diagnosis was performed based on the calcium metabolism and sarcoidosis markers. In cases of suspected ureteric sarcoidosis from the assessment, pathological evaluation with ureteroscopic biopsy should be performed to avoid nephroureterectomy.

Overexpression of LncRNA PSMG3-AS1 Distinguishes Glioblastomas from Sarcoidosis.

In clinical practices, glioblastomas (GBM) in some cases can be misdiagnosed as sarcoidosis. This study aimed to develop a biomarker to distinguish GBM from sarcoidosis. In this study, we found that PSMG3-AS1 was upregulated in plasma of GBM patients in comparison with that in sarcoidosis patients and healthy controls. Receiver operating characteristic (ROC) curve analysis showed that upregulation of PSMG3-AS1 effectively separated GBM patients from sarcoidosis patients and healthy controls. In GBM cells, overexpression of PSMG3-AS1 led to downregulated miR-34a and increased methylation of miR-34a gene. In addition, overexpression of PSMG3-AS1 reduced the inhibitory effects of miR-34a on GBM cell proliferation. In conclusion, overexpression of PSMG3-AS1 distinguishes GBM patients from patients with sarcoidosis, and PSMG3-AS1 may promote GBM cell proliferation by downregulating miR-34a through methylation.

Derangement of Metabolic and Lysosomal Gene Profiles in Response to Dexamethasone Treatment in Sarcoidosis.

Glucocorticoids (GCs) play a central role in modulation of inflammation in various diseases, including respiratory diseases such as sarcoidosis. Surprisingly, the specific anti-inflammatory effects of GCs on different myeloid cells especially in macrophages remain poorly understood. Sarcoidosis is a systemic granulomatous disease of unknown etiology that occurs worldwide and is characterized by granuloma formation in different organs. Alveolar macrophages play a role in sarcoidosis granuloma formation and progressive lung disease. The goal of the present study is to identify the effect of GCs on transcriptomic profiles and the cellular pathways in sarcoidosis alveolar macrophages and their corresponding blood myeloid cells. We determined and compared the whole transcriptional signatures of alveolar macrophages from sarcoidosis patients and blood CD14+ monocytes of the same subjects in response to in vitro treatment with dexamethasone (DEX) via RNA-sequencing. In response to DEX, we identified 2,834 genes that were differentially expressed in AM. Predominant pathways affected were as following: metabolic pathway (FDR = 4.1 × 10-10), lysosome (FDR = 6.3 × 10-9), phagosome (FDR = 3.9 × 10-5). The DEX effect on AMs is associated with metabolic derangements involving glycolysis, oxidative phosphorylation and lipid metabolisms. In contrast, the top impacted pathways in response to DEX treatment in blood CD14+ monocytes were as following; cytokine-cytokine receptor interaction (FDR = 6 × 10-6) and transcriptional misregulation in cancer (FDR = 1 × 10-4). Pathways similarly affected in both cell types were genes involved in lysosomes, cytoskeleton and transcriptional misregulation in cancer. These data suggest that the different effects of DEX on AMs and peripheral blood monocytes are partly dictated by lineage specific transcriptional programs and their physiological functions.

Analysis of soluble interleukin-2 receptor as CSF biomarker for neurosarcoidosis.

OBJECTIVE: To systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis). METHODS: sIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis. RESULTS: Patients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis. CONCLUSIONS: CSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.

Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline.

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

Exploring the imbalance of circulating follicular helper CD4+ T cells in sarcoidosis patients.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease characterized by the combination of Th1 and Th17 responses. Recently, several arguments have suggested a potential involvement of B cells as well as T cells in the pathogenesis of sarcoidosis. Follicular helper CD4+ T (TFH) cells are specialized in interacting with and helping B cells, and play a crucial role in the formation of germinal centers. OBJECTIVE: We sought to explore the status of TFH cells and investigate their possible pathogenic role in sarcoidosis. METHODS: TFH cells and B cells in peripheral blood were examined by flow cytometry, and serum samples were studied by cytokine arrays. Immunohistochemistry was performed to check for the presence of TFH cells in sarcoidosis skin lesions. Gene expression in isolated TFH cells was analyzed by quantitative RT-PCR. RESULTS: The proportion of circulating TFH cells was decreased. CD4+CXCR5+ TFH cells were observed in cutaneous lesions in sarcoidosis. Gene expression in circulating TFH cells and serum cytokine concentrations related to Th17 were increased in sarcoidosis patients. Gene expressions of B cell differentiation cytokines in TFH cells were not altered in sarcoidosis patients. CONCLUSION: We herein describe a decrease of circulating TFH cells and their migration to affected tissues. Circulating TFH cells are one of the potential cell types capable of producing IL-17 and enhancing Th17 responses, and may promote the chronic inflammation. We could not demonstrate a direct linkage between the imbalance of TFH cells and abnormal B cell differentiation in sarcoidosis.

Serum adipokine levels in patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic inflammatory disease characterized by non-caseating granuloma which etiology is unknown yet. Adipokines are different proteins synthesized by adipose tissue that have an influence on angiogenesis, hemostasis, lipid metabolism, and immune system regulation. Adipokines may play a role in the pathogenesis of sarcoidosis. OBJECTIVES: To evaluate the serum adipokine levels in patients with sarcoidosis and to determine a possible correlation with clinical and laboratory signs of disease. METHODS: Forty-four biopsy-proven sarcoidosis patients followed at a single center and age- and sex-matched 41 healthy volunteers were included in the study. Demographic, clinical, laboratory, and radiological data were recorded and body mass index (BMI) was calculated in all patients. Routine laboratory tests (blood glucose, liver, and kidney function test) were measured. Serum adiponectin and leptin levels were measured by ELISA method. RESULTS: Among 44sarcoidosis patients, 13 (29.5%) were male and 31 (70.5%) were female. Twenty-one (47.7%) patients had erythema nodosum, three (6.8%) had uveitis, 40 (90.9%) had arthralgia, 32 (72.7%) had arthritis, 15 (34.1%) had enthesitis. Laboratory evaluation showed increased serum ACE level in 24 (54.5%) patients, increased serum calcium level in 11 (25%) patients, increased serum D3 level in 5 (11.4%) patients, and increased ESR and CRP levels in 22 (50%) and 23 (52.3%) patients, respectively. Compared with the control group, serum adiponectin levels were significantly higher in patients with sarcoidosis(p = 0.007). Serum adiponectin level was associated with arthralgia and ankle joint swelling (p = 0.007, p = 0.006 respectively). Serum leptin levels were similar in sarcoidosis patients and controls (p = 0.327). There was no relationship between serum leptin level and disease features (p > 0.05). CONCLUSIONS: In this study, high serum adiponectin level was detected in patients with sarcoidosis while serum leptin level was similar in the sarcoidosis and control group. Adiponectin, an anti-inflammatory protein, may play a role in the pathogenesis of sarcoidosis. Studies are needed to shed light on this topic.Key Points• Sarcoidosis is a chronic granulomatous disease characterized by granuloma formation• High serum adiponectin level was found in sarcoidosis patients• Serum adiponectin level was associated with some clinical features such as arthralgia and arthritis• High adiponectin levels in sarcoidosis patients may mitigate the inflammatory response, resulting in a mild form of the disease and/or spontaneous remission.